The following discussion of the background of the invention is intended to facilitate an understanding of the present invention. However, it should be appreciated that the discussion is not an acknowledgement or admission that any of the material referred to was published, known or part of the common general knowledge in any jurisdiction as at the priority date of the application.
Sodium channels are the founding members of the superfamily of ion channels that includes voltage gated potassium and calcium channels. Unlike the different classes of potassium and calcium channels, however, functional properties of the known sodium channels (NaV) are relatively similar. Voltage gated sodium site 2 channels which are found in central neurons, are primarily localized to unmyelinated and pre-myelinated axons, govern action potential initiation and repetitive firing. Sodium channels play an important role in the neuronal network by transmitting electrical impulses rapidly throughout cells and cell networks, thereby coordinating higher processes including but not limited to locomotion, cognition and pain. These channels are large transmembrane proteins, which are able to switch between different states to enable selective permeability for sodium ions. For this process an action potential is needed to depolarize the membrane, and hence these channels are voltage-gated.
Voltage-gated sodium channels are classified based on their sensitivity to tetrodotoxin, from low nanomolar (Tetrodotoxin sensitive, TTXs) to high micromolar (Tetrodotoxin resistant, TTXr). So far, 9 different sodium channel α subunits have been identified and classified as NaV 1.1 to NaV 1.9. NaV 1.1 to NaV 1.4, NaV 1.6 and NaV 1.7 are TTXs, whereas NaV 1.5, NaV 1.8 and NaV 1.9 are TTXr, with different degrees of sensitivity. NaV 1.1 to NaV 1.3 and NaV 1.6 are primarily expressed in the central nervous system (CNS), whereas NaV 1.4 and NaV 1.5 are mainly expressed in muscle (skeletal and heart respectively). NaV 1.7, NaV 1.8 and NaV 1.9 are predominantly expressed in dorsal root ganglion (DRG) sensory neurons.
Several diseases, disorders and their symptoms, are related to abnormal sodium channel conductance. These include hyperactivity related, muscular, bladder, immune system, neurological disorders, pain, convulsion, inflammation and even cancer. Voltage-gated sodium channels expressed in non-nervous or non-muscular organs are often associated with the metastatic behaviour of different cancers and have been implicated in the pathology of different cancers such as prostate, breast, lung (small cells and non-small cells) and leukaemia (Roger S et al., Curr Pharm Des 2006, 12(28):3681-3695; Li M and Xiong Z G, Int J Physiol Pathophysiol Pharmacol 2011, 3(2):156-166).
Autism spectrum disorder (ASD) is characterized by social deficits and communication difficulties, stereotyped or repetitive behaviours and hyperactivity. Through whole exome sequencing, candidate genes with de novo mutations, including SCN1A which codes for NaV 1.1, have been recently identified in sporadic ASD (Eijkelkamp et al., Brain, 2012, 135, 2585-2612). Although initially thought to be different, it has been recently found that autism, attention deficit-hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder and schizophrenia, all share common genetic underpinnings (Soretti A and Fabbri C, Lancet, 2013, 381 (9875), 1339-1341). These disorders, their pathophysiology and current treatment are summarized in the fifth revision of the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5), published in 2013, and the Encyclopedia of Psychopharmacology (Springer 2010).
Voltage-gated sodium channel channelopathies such as paramyotonia congenital and periodic paralysis affecting skeletal muscles can be found in SCN4A/NaV1.4. Mutations in NaV 1.4 can result in ionic leak through the gating pore allowing sustained inward sodium flux at negative membrane potentials. Such mutations can also enhance activation or impair inactivation resulting in hyperexcitability (Eijkelkamp et al., Brain, 2012, 135, 2585-2612).
It is believed that changes in the isoforms of sodium channels cause abnormal ectopic firing of the DRG, causing spontaneous ectopic discharges. This can lead to an overactive bladder, characterized by urgency, frequency and nocturia, with or without urge incontinence (Steers W D, Rev Urol 2002, 4 (Suppl4), S7-S18).
In multiple sclerosis, demyelination of axons occur in patients, which lead to ectopic action potential firing that is caused by slow sodium-dependent membrane potential oscillations (Eijkelkamp et al., Brain, 2012, 135, 2585-2612).
Mutations in the gene encoding NaV 1.1 and NaV 1.2 have shown to be involved in the pathophysiology of both acquired and inherited epilepsy, where the active state of sodium channels are favoured, resulting in the potentiation of electrical signal propagation which leads to maximal seizure activity and its spread (Zuliani V. et al., Curr Top Med Chem, 2012, 12(9), 962-70).
A number of drugs having an unknown mechanism of action actually act by modulating sodium channel conductance, including local anesthetics, class I antiarrhythmics and anticonvulsants. Ion channel targeted drugs have always been related with either the CNS, the peripheral nervous system, or the cardiovascular system (Waszkielewicz A M et al., Curr Med Chem, 2013, 20, 1241-1285). Neuronal sodium channel blockers have found application with their use in the treatment and alleviation of the abovementioned diseases, disorders and symptoms, for example, epilepsy (phenyloin and carbamazepine), bipolar disorder (lamotrigine), preventing neurodegeneration, and in reducing neuropathic pain. Various antiepileptic drugs that stabilize neuronal excitability are effective in neuropathic pain (e.g. carbamazepine).
However, there is still a need for improved methods and compounds in treating and alleviating sodium channel related diseases, disorders and symptoms, for example lowering dosage but maximising drug effects in addressing these diseases, disorders and symptoms.
Threo- and erythro-diastereomers of methylphenidate are known to bind to dopamine and serotonin receptors, where the threo form is commonly prescribed to patients as a racemate for the treatment of ADHD (Davies H. M. L. et al., Bioorg Med Chem Lett, 2004, 14, 1799-1802). This is iterated in WO 2007106508 A2 where methylphenidate also interacts with norepinephrine, serotonin and dopamine transporters, most of them in the micromolar range. However, the present inventors have found that methylphenidate and its analogues, strongly bind to sodium channels, in particular to sodium channel site 2—this is not disclosed nor suggested in the prior art. Further, the IC50 values for the antagonistic binding activity of the compound in WO 2007106508 A2 to serotonin 5-HT2A and 5-HT2C receptors are in the micromolar range, which should not be sufficient to elucidate the desired pharmacological effects. Moreover, the synthesis of the methylphenidate analogues in WO 2007106508 A2 involve a rhodium catalyst which will be an issue in an active pharmaceutical product since the amount of heavy metals is strictly regulated and is limited to rhodium at 10 ppm for oral dosing and 1 ppm for parental administration.
Therefore the object of the present invention is to provide for an improved use of methylphenidate analogues for the treatment of sodium channel related diseases and disorders. The present invention also provides an improved process of synthesizing methylphenidate analogues to increase the safety and efficacy of the resultant compounds.